Spanish building regulations have increased the ventilation rates creating humidity control problems. Dedicated outdoor air systems (DOASs) including a desiccant wheel can dry the ventilation air so that the cooling units are relieved of the latent loads carried by the ventilation air and those generated inside the building. The purpose of this study was to compare the performance of two different DOAS configurations in terms of primary energy consumption under different Spanish climates. The DOAS comprising a desiccant wheel and a conventional refrigeration system was called DOAS-A. The DOAS comprising a desiccant wheel regenerated by solar air collectors and an indirect evaporative cooler was called DOAS-B. The performance of both DOASs was simulated with TRNSYS, and the models were validated with data from experimental setups built at the Miguel Hernandez University of Elche (Spain) and at the Technical University of Cartagena (Spain). It was found that the DOAS-B configuration consumed less primary energy than the DOAS-A configuration for commercial use, that is, when the latent load coincides with the supply of solar radiation. These savings reached 68.3% in Seville owing to its high level of solar radiation. It was also found that the net sensible load supplied by the ventilation air to the conditioned space was negative for all climates. This sensible cooling capacity was shown to be greater at lower outdoor dry-bulb temperature and lower latent load.